Human immunodeficiency-virus(HIV) encephalitis and vacuolar myelopathy (VM) are among the most common diseases of the brain and spinal cord in patients with the acquired immunodeficiency syndrome (AIDS). However, the mechanisms by which CNS injury occurs in these two disorders are incompletely understood. Although HIV encephalitis (HIVE) correlates well with brain atrophy and with AIDS dementia, atrophy and dementia is not always accompanied by HIV. Vascular myelopathy (VM), the most common cause of myelopathies in AIDS, is clearly associated with HIVE, yet a number of studies, including our own, indicate that it is not due to a direct HIV myelitis. The work completed during the current funding period highlights three potential mechanisms that may be important: a chronically-opened blood brain barrier (BBB) in the cerebral white matter; the identification of programmed cell death (apoptosis) in the cerebral grey matter; a close association between VM and HIVE. The following hypotheses and specific aims will further explore these mechanisms. 1. The diffuse white matter changes in brains of HIV- infected patients are due to a chronically-opened blood-brain barrier. 2 The BBB breakdown is due to and follows endothelial activation and occurs through vesicular transport in cerebral venules. 3. Diffuse white matter changes in brains of HIV-infected patients are secondary to a chronically-opened blood-brain barrier rather than by direct HIV infection. 4. The neuronal loss in AIDS brains is due to programmed cell death (apoptosis), mediated via activated, HIV-infected microglia and is the cause of AIDS dementia. 5. The etiology of VM is multifactorial and includes vitamin B12 deficiency as well as by indirect effects of HIV encephalitis. These hypotheses will be examined in brains of AIDS patients with or without HIVE and VM and in a nude mouse model of TNF toxicity induced by intramuscular or intracerebral inoculations of a TNF-producing tumor cell line. Techniques to be used include immunohistochemistry, in situ end labeling of DNA fragments, light and electron microscopy and BBB tracer and transport studies. The results of the proposed projects will clarify the cellular mechanisms whereby brain and spinal cord damage occur in HIV infection, establish the etiology of VM and offer the potential for therapeutic interventions of TNF-induced BBB breakdown or tissue damage, apoptosis or vitamin deficiency.